Ester of 2-carboxy-5-aminodiphenyl



Patented a. s, 1934 UNITED sr ESTER 0F 2-OARBOXY-5-AMIN DIPHENYL Williams. Jones and illiam Bram, Brooklyn,

Brooklyn assignors to E. R. Squibb eaSons,

, N. Y., a corporation of New York No Drawing. Amflication September 12,1932, Serial No. 632,789

18 Claims. (01. 167-52)- This invenion relates to esters of 2-carboxy-S-amino-diphenyl, such as the dialkyl-aminoalkyl esters of2-carboxy-5-amino-diphenyl and salts of these esters; more particularlyit relates I to 2-p-diethyl-amino-carbethoxy-5-amino "di phenyl, 2---di-n-butyl-amino-carbopropoxy-5- amino diphenyl and their salts. Itincludes both the new compounds and therapeutically active mixturescontaining these compounds.

The new compounds of this invention may be prepared from 2carboxyfi-amino diphenyl which is claimed as anew product in ourcopending application Serial No. 589,039, filed J anuary 26, 1932. Bydissolving this compound and sodium in absolute alcohol and causing thesalt thus formed to react with ya dialkyl-amino substituted alkyl halidedissolved in absolute alcohol, the dialkyl-amino-carbalkoxy-amino-diphe-I nyls of this invention can readily be prepared. 2 The intermediate isadvantageously prepared by diazotizing 2-amino-5-nitro-diphenyl inconcentrated acid solution, then forming the nitrile by treating thediazonium salt with a cyanide, hydrolizing the nitrile and then reducingthe nitro group.

The dialkyl-amino substituted side chain may be a straight chain or abranched chain. The following equation indicates various intermediatesformed at various steps in the preparation of these compounds and givesa general formula for the end'product where R is an alkylene radical andR1 and R2 are the same or different alkyl radicals.

I of the invention, but it is to be understood that vin 250 cc. ofwater.

b- H, 0N coon pm I cm the invention is not limited thereto. The '2-amino-5-nitro-diphenyl which is used. as the starting material may beprepared by the method given in the Journal of the Chemical Society,

vol. 2, 1928. page 2774, or preferably by hydrolysis 0 of5-nitro-2-para-toluene sulione amido diphenyl.

50.0 grams of 2-amino-5-nitro-diphenyl is suspended in 130 cc. ofconcentrated hydrochloric acid. This suspension. is diazotized with 21.5grams of sodium 'nitrite contained in cc. of water. The diazoniumsolution is then added at -10 to 0 C. to a solution of potassium coppercyanide The latter is prepared by adding 120 grams of potassium cyanidein 250 cc. of 79 water to 100 grams of crystalline copper sulfate Theaddition of diazonium solution is made over a period of 30 minutes whilestirring. The suspension thus obtained is stirred at 0 for one hour whenthe temperature is gradually raised to 20 C. and held at thistemperature for one-half hour. The suspension is then slowly heated to90 C. After heating for 3 hours at 90 C., the reaction mixture iscarefully alkalinized with 150cc. of 40% sodium hydroxide 30 solution. e

' The precipitate formed as a result of the reaction is filtered off,washed with water and dried in vacuo. The crude nitrile is crystallizedtwice from alcohol. The melting DOint of the 2-cyanofi-nitro-diphenylwas found to be 131-l33 C.

5.2 grams of the nitrile is suspended in a solution consisting of 75 cc.of glacial acetic acid, 60 cc. of sulfuric acid. and 50 cc. of water.The mixture is refluxed for about eight hours. The resulting solution isdiluted with an equal volume of water. The hydrolysis of the nitrileproduces a crystalline substance which is filtered oil. This compound iswashed with water and dried in vacuo. It is the2-carboxy-5-nitrc-diphenyl.

3.0 grams of the 2-carboxy-5-nitro-diphenyl are reduced with 10.0 gramsof tin and 50 cc. of hydrochloric acid. The reduction is carried on forthree hours and the tin is then precipitated out as the sulfide. Thesulfide is filtered 01! and the 10 filtrate evaporated tosinall volume.

4.5 grams of the crudehydrochloride is dissolved in 20 cc. ofconcentrated hydrochloric acid and 30 cc. of alcohol at 80 C. Thissolution is shaken with 5.0 grams of decolorizing charcoal whitecrystals of 2-carboxy-5-amino-diphenyhll0 hydrochloride which arecollected by filtration. sucked as dry as possible and dried in vacuo.

1.2 grams of the hydrochloride 0! 2-carboxy- 5-amino-diphenyl aredissolved in 20 cc. oi! absolute alcohol. 0.22 grams or sodium dissolvedin .20 cc. of absolute alcohol are added to the above solution. Sodiumchloride formed by neutralization of the hydrochloride with the sodiumethoxide is filtered from the alcoholic solution. 1.0 grams ofdiethyl-amino ethyl-chloride are dissolved in 10 cc. of absolute alcoholand added to the solution of the sodium salt of 2-carboxy-5-amino-diphenyl. An immediate precipitation or sodium chloride appears.The solution is refluxed for seven hours; the sodium chloride is removedby filtration and the solvent and excess p-diethyl-amino-ethyl-chlorideare removed from the filtrate by distillation in vacuo. The light yellowoil remaining after the complete removal 01' the solvent and excessdiethyl-amino-ethylchloride is the 2-p-diethyl-amino-carbethoxy-5-amino-diphenyl.

The dihydrochloride of the 2-s-diethyl-aminocarbethoxy-fi-amino-diphenylis prepared by passing dry hydrochloric acid gas into an etherealsolution of the free base. This separates as a yellow oil from which theether layer is decanted.

The yellow oil is then heated in an oven at'100 C. It is then placed ina dessicator containing NaOH sticks and calcium chloride- Thedihydrochloride thus obtained is a yellowish white substance which isextremely hygroscopic.

Llgrams of the hydrochloride of 2-carboxy-5- amino-diphenyl prepared asabove described, or by any suitable process, is dissolved in 20 cc. oiabsolute alcohol. 0.2 grams of sodium in 20 cc. of alcohol is added. Thesodium chloride formed is filtered off. The filtrate is added to asolution consisting of 0.92 grams of di-n-butyl-aminopropyl chloride in30 cc. of alcohol. A precipitate of. sodium chloride becomes evidentafter refluxing for 10 minutes. The solution is refluxed for 7 hours.The salt formed as a result of the reaction is filtered off and thefiltrate is distilled on the steam bath to remove the solvent. Theresidue is a dark, brown oilwhich is the 2-7411-11- butyl-aminocarbopropoxy-5-amino-diphenyl.

The dihydrochloride oi Z-din-butyl-amino carbopropoxy-5-amino-diphenylis prepared by adding a slight excess of hydrochloric acid to analcoholic solution of the base and evaporating to dryness in vacuo. Aglassy, dark brown sub- 2-p-diethyl-amino-carbethoxy-5-aminc-diphenyl orone or the other esters or this invention when usedas an anesthetic willtherefore ordinarily be convertedto a salt such as may be formed bysolution in a suitable quantity of an inorganic or organic acid, and beadministered in aqueous solution when the dihydrochloride or other'highly acid salt is used as an anesthetic the optimumresultsare'obtained by buffering the solution with a phosphate or otheralkaline salt.

7 Other salts such as the borate, etc., yield solutions of satisfactoryhydrogen ion concentration sothat buffering is not needed. 7

Other diallrvl-amino-alkyl esters of Z-carboxy- 5-amino-diphenyl may beprepared in a similar manner by coupling the sodium salt 01 2-carboxy-5-amino-diphenyl with other dialkyl-amino-alkyl-halides.s-dimethyl-amino-ethyl chloride will give the2-p-dimethyl-amino-carbethoxy-5- amino-diphenyl.p-ethyl-methyl-amino-ethylchloride will give theZ-B-ethyI-methyl-aminocarbethoxy-B-amino-diphenyl. Instead of adialkyl-amino-ethyl-chloride the dialkyl-amino derivatives of otheralkyl chlorides may be employed, such as the dialkyl-amino derivativesof the propyl, butyL'etc. chlorides. Derivatives of both normal,secondary and tertiary chlorides may be employed. For example,p-chlor-alphadiethyl-amino-propane, .CH3.CHC1.CH:.N (CzHs) when coupledwith the sodium salt of 2-carboxy- E-amino-diphenyl will give:

ooo-omom-om-momo,

oooonm-mtm,

HtN

where R1 and R2 are the same or different C O O-R-NBiB:

where R is an alkylene group and R1 and R: are the same ordifierentalkyl radicals.

6. A compound from the group consisting of2-s-diethyl-amino-carbethoxy-5-amino-diphenyl and inorganic saltsthereof.

'1. A compound from the group consisting of Z- y-di-n -butyl -aminocarbopropoxy 5 amino diphenyl and inorganic salts thereof.

. 8. 2-p-diethyl amino carbethoxy-5-amino-diphenyl.

.9. The dihydrochloride or 2--y-di-n-butyl-amino-carbopropoxy-iamino-diphenyl.

10. An anestheticcomposed in part or a di- 15. An anesthetic composed ofthe dihydroalkyl-amino-alkyl ester or z-carboxy-s-amincchloride of2-,6-diethyl-amino-ce.rbethoxy-5-amino-diphenyl and a phosphate inaqueous solution.

16. The borate of a dialkyl-amino-alkyl ester of2-carboxy-5-amino-diphenyl.

1'1. Inorganic salts of the dialkyl-amino-alkyl esters of2-carboxy-5-amino-diphenyl.

18. The hydrochlorides of the dialkyl-aminoalkyl esters ofZ-carboxy-fi-amino-diphenyi.

WILLIAM S. JONES. WILLIAM BRAKER.

